Enzyme inhibitors urokinase

Emonard, H. and Grimaud, J-A. (1990). Matrix metal-loproteinases a review. Cell Mol. Biol. 4, 195-203. Estreicher, A., Muhlhauser, J., Carpentier, J-L., Orci, L. and Vassalli, J-D. (1990). The receptor for urokinase plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes d radation of enzyme-inhibitor complexes. J. Cell Biol. Ill, 783-792. Evans, M.J. and Plopper, C.G. (1988). The role of basal cells in adhesion of columnar epithelium to airvray basement membrane. Am. Rev. Respir. Dis. 138, 481—483. 

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Plasminogen activator inhibitors have been shown to be present in a large variety of different cells and tissues. These inhibitors are thought to play an important role in regulating tissue fibrinolysis. One of these inhibitors has been purified from cultured bovine aortic epithelial cells. This inhibitor has been shown to be a serine protease inhibitor and inhibits the function of two proteolytic enzymes urokinase and tissue plasminogen activator, both of which cleave and activate plasminogen. The mechanism by which this inhibitor functions is very similar to that described above with a-l-PI. Thus, the inhibitor forms a binary complex with the proteolytic enzyme and thereby inhibits its activity. Again in a situation comparable to that with a-l-PI, it was found that when the purified bovine aortic epithelial inhibitor was exposed to Al-chlorosuccinimide,... 

After the nucleophilic attack by the hydroxyl function of the active serine on the carbonyl group of the lactone, the formation of the acyl-enzyme unmasks a reactive hydroxybenzyl derivative and then the corresponding QM. The cyclic structure of the inhibitor prevents the QM from rapidly diffusing out of the active center. Substitution of a second nucleophile leads to an irreversible inhibition. The second nucleophile was shown to be a histidine residue in a-chymotrypsin28 and in urokinase.39 Thus, the action of a functionalized dihydrocoumarin results in the cross-linking of two of the most important residues of the protease catalytic triad. 

The hypothesis that stress can modulate MMP expression is also supported by studies in mice. Using social isolation as a stressor, the mRNA levels of MMP-2, MMP-9, matrix-type matrix metalloproteinase-1 (MT1-MMP), and urokinase-type plasminogen activator were higher in the tumor and liver tissues of the isolated mice than in control mice.91 Furthermore, a recent study has shown that restraint stress causes an increase in expression of the plasminogen activator inhibitor-1, another key player in the plas-minogen/plasmin enzyme system in mice.92 As these enzymes have been described to have functions besides their role in ECM remodeling,93 studies on stress-related effects on MMP/TIMP balance have implications in the relationship between stress and cancer initiation and progression.. 

Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects. However, the absence of inhibitors for urokinase and the streptokinase-proactivator complex permits their use clinically. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within. 

The enzymatically inactive acyl-urokinase was reactivated in plasma at 37°C with a reactivation half-time of 8 minutes (benzoyl-urokinase) or 10 hours (p-guanidinobenzoyl-urokinase). Upon administration to rabbits, urokinase was more rapidly eliminated than either acyl enzyme (Fig. 11). The results suggest that urokinase is eliminated via the binding to plasma inhibitors. Thus, it could be shown that the clearance of urokinase is modified significantly on acylation. 

Sweep, C. G. J., Geurts-Moespot, J., Grebenschikov, N., et al.. External quality assessment of trans-european multicenter antigen determination (enzyme-linked immunosorbent assay) or urokinase plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) in human breast cancer extracts. Br. J. Cancer 78, 1434-1441 (1998). 

In the pathogenesis of pulmonary fibrosis, the injury to the alveolar membrane is followed by an exudation of seram proteins into the alveolar space that ultimately leads to the formation of a fibrin- rich extracellular matrix. During this initial stage, the activation of plasmin, the enzyme primarily responsible for fibrin degradation, is impaired as the result of an imbalance between urokinase plasminogen activator (uPA) and this latter enzyme s primary inhibitor, plasminogen activator inhibitor-1 (PAI-1) (9,10). In human fibrotic lung disease and in the bleomycin rodent model of pulmonary fibrosis, PAI-1 erqjtession is markedly... 

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